In the United States, one in eight women will be diagnosed with breast cancer. Breast cancer is a heterogeneous disease which can be segregated into subtypes based on clinical and molecular features, and these subtypes strongly associate with clinical outcome. The subtype with the worst prognosis is triple- negative breast cancer, which is characterized by absence of the estrogen and progesterone receptors, and HER2/neu. Elevated hypoxia-inducible factor 1-alpha (HIF11) protein levels, in addition to overexpression of HIF1-target genes, statistically correlate to malignancy and poor prognosis, and in this proposal, I demonstrate that elevated HIF11 protein levels are a signature of triple-negative breast cancer. I plan to use a combination of in vitro and in vivo assays to understand the function of HIF11 in triple-negative breast cancer tumorigenesis. First, I will determine whether the elevated HIF11 protein levels are a result of increased stability due to diminished prolyl hydroxylase-activity. Then I will determine whether HIF11 is sufficient and/or necessary to drive breast cancer proliferation in vitro, and tumorigenesis in vivo. The goal of the current proposal is to address the mechanism by which the increased expression of HIF11 occurs, and to characterize HIF11 as a therapeutic target in triple-negative breast cancer. This work might eventually lead to the use of HIF1-antagonists in the clinic for the treatment of triple-negative breast cancer. PUBLIC HEALTH RELEVANCE: The work described in this proposal will greatly enrich our understanding of the role of HIF11 in mammary tumorigenesis, specifically in triple-negative breast cancer. Triple-negative breast cancer is the subtype with the worst prognosis, and does not have a highly-effective therapy. This work might facilitate the development of specific therapies that target HIF11 and/or the HIF1-responsive pathway, and provide a novel therapeutic strategy for triple-negative breast cancer.